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Abstract
Antibiotic resistance is a pressing global health problem that threatens millions of lives each year. Natural antimicrobial peptides and their synthetic derivatives, including peptoids and peptidomimetics, are promising candidates as novel antibiotics. Recently, the C-terminal glycine-rich fragments of human epithelial keratin 6A were found to have bactericidal and cytoprotective activities. Here, we used an improved 2-dimensional NMR method coupled with a new protocol for structural refinement by low temperature simulated annealing to characterize the solution structure of these kerain-derived antimicrobial peptides (KAMPs). Two specific KAMPs in complex with membrane mimicking sodium dodecyl sulfate (SDS) micelles displayed amphipathic conformations with only local bends and turns, and a central 10-residue glycine-rich hydrophobic strip that is central to bactericidal activity. To our knowledge, this is the first report of non-αβ structure for human antimicrobial peptides. Direct observation of Staphylococcus aureus and Pseudomonas aeruginosa by scanning and transmission electron microscopy showed that KAMPs deformed bacterial cell envelopes and induced pore formation. Notably, in competitive binding experiments, KAMPs demonstrated binding affinities to LPS and LTA that did not correlate with their bactericidal activities, suggesting peptide-LPS and peptide-LTA interactions are less important in their mechanisms of action. Moreover, immunoprecipitation of KAMPs-bacterial factor complexes indicated that membrane surface lipoprotein SlyB and intracellular machineries NQR sodium pump and ribosomes are potential molecular targets for the peptides. Results of this study improve our understanding of the bactericidal function of epithelial cytokeratin fragments, and highlight an unexplored class of human antimicrobial peptides, which may serve as non-αβ peptide scaffolds for the design of novel peptide-based antibiotics.
Highlights
Antimicrobial resistance is a major public health problem posing deadly threats to the global community
It has been reported that the hydrophobic portions of classic amphipathic helices penetrate into the interior of sodium dodecyl sulfate (SDS) or dioctanoylphosphatidylglycerol (D8PG) micelle cores, while the cationic amino acids such as arginines directly interact with the anionic headgroups (Wang et al, 1996; Wang, 2008)
We reported that bactericidal fragments of keratin 6A (KAMPs) have neutral or modest positive charge and are expressed in stratified epithelial cells, suggesting a novel, direct antimicrobial function for keratins in epithelial innate defense against infection
Summary
Antimicrobial resistance is a major public health problem posing deadly threats to the global community. Production of antimicrobial peptides (AMPs) by epithelial cells and local phagocytes provides a crucial innate defense mechanism guarding the host barriers against microbial invasion. They are produced by virtually all organisms from bacteria to vertebrates and are best known for their direct and fast-acting microbicidal activity (http://aps.unmc.edu/AP) (Wang et al, 2016). These host defense peptides, primarily defensins and cathelicidins, are short (12-50 amino acids), polycationic, amphipathic peptides possessing α-helical and/or β-sheet structures critical for their antimicrobial activities (Wang, 2014). With advanced technologies in synthesis, functional design and modification of synthetic analogs, cationic AMPs and their modified derivatives are being recognized as promising anti-infective candidates, including six compounds currently in phase I-III clinical trials (Fox, 2013)
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